TY - JOUR
T1 - The Transcription Factor AP4 Mediates Resolution of Chronic Viral Infection through Amplification of Germinal Center B Cell Responses
AU - Chou, Chun
AU - Verbaro, Daniel J.
AU - Tonc, Elena
AU - Holmgren, Melanie
AU - Cella, Marina
AU - Colonna, Marco
AU - Bhattacharya, Deepta
AU - Egawa, Takeshi
N1 - Funding Information:
We thank B.P. Sleckman for c-MYC-GFP mice; F.W. Alt for Myc F mice; E. Oltz for Cd79a icre/+ mice; J.M. White for ES cell microinjection; S. Hsiung, Y. Wang, R. Wong, and S. Faragasan for technical support; and C.-S. Hsieh, K.M. Murphy, and E. Oltz for discussion. This study was supported by the Lucille P. Markey Pathway Program (C.C.), the NIH (P30 AR048335 to the Rheumatic Diseases Core Center; R01 AI097244 and R56 AI114593 to T.E.; R01 AI099108 to D.B.; UL1 TR000448 to the Washington University Institute of Clinical and Translational Sciences; P30 CA91842 to the Siteman Cancer Center), and the Edward Mallinckrodt Jr. Foundation (T.E.). D.B. is a New York Stem Cell Foundation-Robertson Investigator.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/9/20
Y1 - 2016/9/20
N2 - B cells diversify and affinity mature their antigen receptor repertoire in germinal centers (GCs). GC B cells receive help signals during transient interaction with T cells, yet it remains unknown how these transient T-B interactions in the light zone sustain the subsequent proliferative program of selected B cells that occurs in the anatomically distant dark zone. Here, we show that the transcription factor AP4 was required for sustained GC B cell proliferation and subsequent establishment of a diverse and protective antibody repertoire. AP4 was induced by c-MYC during the T-B interactions, was maintained by T-cell-derived interleukin-21 (IL-21), and promoted repeated rounds of divisions of selected GC B cells. B-cell-specific deletion of AP4 resulted in reduced GC sizes and reduced somatic hypermutation coupled with a failure to control chronic viral infection. These results indicate that AP4 integrates T-cell-mediated selection and sustained expansion of GC B cells for humoral immunity.
AB - B cells diversify and affinity mature their antigen receptor repertoire in germinal centers (GCs). GC B cells receive help signals during transient interaction with T cells, yet it remains unknown how these transient T-B interactions in the light zone sustain the subsequent proliferative program of selected B cells that occurs in the anatomically distant dark zone. Here, we show that the transcription factor AP4 was required for sustained GC B cell proliferation and subsequent establishment of a diverse and protective antibody repertoire. AP4 was induced by c-MYC during the T-B interactions, was maintained by T-cell-derived interleukin-21 (IL-21), and promoted repeated rounds of divisions of selected GC B cells. B-cell-specific deletion of AP4 resulted in reduced GC sizes and reduced somatic hypermutation coupled with a failure to control chronic viral infection. These results indicate that AP4 integrates T-cell-mediated selection and sustained expansion of GC B cells for humoral immunity.
UR - http://www.scopus.com/inward/record.url?scp=84990877410&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2016.07.023
DO - 10.1016/j.immuni.2016.07.023
M3 - Article
C2 - 27566940
AN - SCOPUS:84990877410
SN - 1074-7613
VL - 45
SP - 570
EP - 582
JO - Immunity
JF - Immunity
IS - 3
ER -